Malarial disease, caused by Plasmodium species, remains an unresolved global health burden that impacts >40% of the world's population. Although the availability of insecticide treated bed nets and antimalarial drugs has reduced the incidence and severity of malaria in some regions, ~200,000,000 cases still occur annually with ~850,000 fatalities in 2013. Thus, vaccines to prevent malaria remain an as yet unrealized but critical goal to combat this global threat. As shown in our preliminary data, only some of Plasmodium antigens that elicit CD8 T cell responses were targets of CD8 T cell mediated sterilizing immunity. Aim 1 will address the mechanisms that determine whether a specific Plasmodium antigen is the target of effective protection by memory CD8 T cells. Information generated from this aim will provide a practical basis to select new candidate antigens, from the expressed pool of ~5,000 ORF, for evaluation as subunit vaccines to protect against human malaria. Importantly, despite repeated exposures, sterilizing immunity (defined as prevention of blood-stage parasitemia after sporozoite infection) does not develop in individuals living in malaria endemic areas. Indeed our preliminary data reveal both numerical and functional impairment of memory CD8 T cells generated during malaria infection. In aim 2, we will use our newly developed tool-chest, including TCR-retrogenic mice specific for recently identified Plasmodium antigens, to determine how memory CD8 T cells generated after malaria infection are numerically and functionally impaired. Our long-term goal is to understand the mechanisms underlying protective CD8 T cell immunity to liver- stage Plasmodium infection in order to aid in the rational development of effective vaccines. SA 1. Determine why some, but not all Plasmodium antigens are targets of protective CD8 T cells. SA2. Determine the mechanism(s) by which Plasmodium infection results in compromised memory CD8 T cell populations.